FI66372B - FRAMEWORK FOR THE PHARMACOLOGICAL PROCESSING OF THE PHARMACOLOGICAL NETWORK I 5-ELLER 6-STATIONARY MEDIUM PYRIDAZINONRING SUBSTITUERADE BESIMIDAZOLER - Google Patents

Description

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Patent · och reglsterstyreleen Anabkanutbtfdochuti jkrtft1n publtcarxl iy.uo.on (32) (33) (31) Pyrdttr «wort» · »Begird prlorket 25.08.78 01.06.79 Federal Republic of Germany1 Förbunds-republiken Tyskland (DE) P 2937161 (71) Dr. Karl Thomae Gesellschaft mit beschränkter Haftung, Biberach an der Riss, Federal Republic of Germany (DE) (72) Volkhard Austel, Biberach, Joachim Heider, Warthausen,

Wolfgang Eberlein, Biberach, Willi Diederen, Biberach,

Walter Haarmann, Biberach, Federal Republic of Germany Förbundsrepubliken Tyskland (DE) (710 Leitzinger Oy (52) Method for the preparation of pharmacologically active benzimidazoles substituted at the 5- or 6-position by a pyridazinone ring - Förfarande för framstä11 Ning av pharmacologiskt verk pyridazinone ring substituents benzimidazoler

The present invention relates to a process for the preparation of pharmacologically active benzimidazoles of the formula I which are substituted in the 5- or 6-position by a pyridazinone ring.

R B R3 j

/ V <tV

2 A wherein A and B are each a hydrogen atom or together another bond, R 1 is a hydrogen atom, a trifluoromethyl group, an alkyl group having 1 to 11 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a hydroxy group optionally substituted by an alkyl group having 1 to 6 carbon atoms. or a mercapto group, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, or a phenyl group which may be mono-, di- or trisubstituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms, methylsulfinyl, hydroxy, mecapto, methylmercapto and / or or an alkoxy group which 66372 and group I contains 1 to 6 carbon atoms, 1 * 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a 3 to 6-yl atom! a cycloalkyl group or a phenylalkyl group having an alkyl moiety 1 to 3 carbon atoms, and is an alkyl group having 1 to 6 carbon atoms, and their physiologically acceptable acid addition salts with inorganic or organic acids.

The compounds of the general formula I and their physiologically acceptable acid addition salts have valuable pharmacological properties. In addition to their antiviral, interferon and antiulcer effects, they have, in particular, cardiovascular effects, namely cardiotonic, antihypertensive and / or antithrombotic effects.

According to the invention, the novel benzimidazoles are prepared by the following process alternatives: a) Cyclization of a compound of general formula II, optionally prepared in a reaction mixture

B

X R3 I

H ”* ΙΤ)

Y

wherein A, B, R 1 and R 3 are as defined above, and one of X or Y is a hydrogen atom and the other of X or Y or both X and Y is a group of formula 3 66ι 66 / ζ2 66372 c - R4 where Z1 Z2 O 2 may be the same or different, mean an optionally substituted amino group or a hydroxy or mercapto group optionally substituted by lower alkyl groups, or Z 2 and Z 2 are - together with an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms , an alkylenedioxy or alkylenedioxy group having in each case 2 or 3 carbon atoms and means the same as the group R 1 above or an amino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, or an alkali salt thereof when R 1 is a mercapto group.

The cyclization is conveniently carried out in a solvent such as ethanol, isopropanol, glacial acetic acid, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, for example, in the preparation of CN, (R 2 CO 2 O, R 2 COOH, R 2 C 5 OH or R 2 CSSH and their esters, orthoesters, amides, halides or methiodides, at elevated temperatures, for example between 0 and 250 ° C, optionally with a condensing agent such as phosphorus oxychloride, in the presence of thionyl chloride, sulfuryl chloride, sulfuric acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid, glacial acetic acid, acetic anhydride or optionally also a base such as potassium methylate or potassium tert-butylate.

However, it is particularly preferred to carry out the reaction in such a way that the corresponding 6- (acylamino-nitro-phenyl) -pyridazin-3-one is converted into the corresponding compound of general formula II by reduction, for example by reduction with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium / carbon. by reduction with metals, 4 66372 such as iron, tin or zinc or by reduction with metal salts such as ferrous sulphate 11a, stannous chloride 11a or chromium (II) chloride or by reduction with hydrazine in the presence of Raney nickel. This compound of general formula II is optionally cyclized in the same reaction mixture, if necessary, in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid or a carboxylic acid of formula R-COOH or in the presence of a condensing agent such as phosphorus oxychloride or a base such as potassium ethylate. in isopropanol, glycol, dimethylformamide, dimethyl sulfoxide or chlorobenzene at temperatures between 0 and 250 ° C.

To prepare a compound of general formula I wherein R 1 is a mercapto group, the reaction is conveniently carried out by preparing the compound of general formula II in situ by reacting the corresponding 7,8-diamino compound with carbon disulfide in the presence of an alkali metal alcoholate, for example potassium ethylate, in an alcoholic solvent such as in the presence of ethanol. The cyclization is then performed simply by heating the reaction mixture, preferably by heating the reaction mixture to boiling point.

b) Carboxylic acid of general formula III O A B N ·. . -

// I, -1- C - C - CH - COOH

AA; N X r 3 R 2 wherein A, B, R 1, R 2 and R 3 are as defined above, or an ester, amide or halide thereof is reacted with hydrazine.

The reaction is conveniently carried out in a solvent such as ethanol, isopropanol, glacial acetic acid, propionic acid and / or an excess of hydrazine or hydrazine hydrate, at elevated temperatures, for example between 0 and 150 ° C, and optionally with a condensing acid such as sulfuric acid. or in the presence of p-toluenesulfonic acid. However, the reaction can also be carried out without a solvent.

The compound of general formula I obtained by process a) or b) in which A and B are each a hydrogen atom can then, if desired, be converted by dehydration into a compound of general formula I in which A and B together are another bond and / or a compound of general formula I in which R R 1 is a hydroxy or mercapto group or a phenyl group mono-, di- or tri-substituted by a hydroxy and / or mercapto group and / or R 1 is a hydrogen atom is converted by alkylation into the corresponding alkoxy, alkyl mercapto and / or alkyl compound of the general formula I, and / or the resulting compound of general formula I wherein R 1 is a phenyl group substituted by at least one alkyl mercapto group is converted by oxidation to the corresponding alkylsulfinylphenyl compound of general formula I, and / or the obtained compound of general formula I wherein R 1 is an alkylmercapto group is converted by oxidation and by cleavage of the hydrolytically formed alkylsulfinyl or alkylsulfonyl group to give the corresponding formula To a hydroxy compound of formula I.

Subsequent dehydration is performed with a dehydrating agent such as bromine, phosphorus pentachloride, 3-nitrobenzenesulfonic acid sodium, chromium trioxide, N-bromosuccinimide, hydrogen peroxide or sodium nitrite at 100 ° C in a solvent such as glacial acetic acid, glacial acetic acid, between 50 and 80 ° C.

Subsequent alkylation is performed with an alkylating agent such as an alkyl halide, dialkyl sulfate, trialkyloxonium tetrafluoroborate or diazoalkane, for example methyl iodide, dimethyl sulfate, in ethanol or ethanol, in methanol, diethyl sulfate, ethyl bromide or diazo-methane, , optionally in the presence of a base such as sodium bicarbonate, sodium carbonate, 66372 sodium hydroxide, sodium methylate or potassium carbonate, up to the boiling point of the solvent used.

Subsequent oxidation is conveniently carried out in a solvent such as glacial acetic acid or trifluoroacetic acid and conveniently using an equivalent oxidizing agent such as hydrogen peroxide if the alkylsulfinylphenyl compound is prepared at temperatures between 0 and 50 ° C, but preferably at room temperature.

The obtained compounds of general formula I in which A and B are each a hydrogen atom can be further separated into their optically active antipodes by racemate cleavage. The racemate cleavage is conveniently carried out by fractional crystallization of the corresponding salt with optically active acids such as tartaric acid, dibenzoyltartaric acid, malic acid, camphoric acid or camphorsulfonic acid.

The obtained compounds of the general formula I can furthermore, if desired, be converted into their physiologically acceptable salts with inorganic or organic acids. Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

The compounds of the general formulas II and III used as starting materials are obtained by methods known from the literature (see British Patent 1,466,547). Thus, for example, a compound of general formula III is obtained by reacting a compound of general formula IV

Cl - ^ CO - CH - Hal (IV) R3 to react with malonic ester. The compound thus obtained is then saponified, decarboxylated, nitrated, the chlorine atom replaced with the corresponding amino group, acylated, the nitro group reduced and cyclized to the desired benzimidazole.

7 66372

The compounds of the present invention differ from the compounds of Finnish Patent Publication No. 59408 in that the alkyl substituents are in the 5-position of the pyridazine ring. In addition, the new benzimidazoles surprisingly have a higher potency and / or better oral resorption. Thus, as already mentioned above, the novel compounds of the present invention have better pharmacological properties, i.e., organic resorption, i.e. in addition to the antiviral, interferon-inducing and anti-ulcer effect, in particular the cardiovascular properties, namely the cardiotonic, antihypertensive and / or antithrombotic effect.

The biological properties of, for example, the following compounds, of which compounds A-R are compounds of formula I, and compounds S-W are known from Finnish Patent Publication No. 59408, were examined as described below.

A - 2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, B = 2-methyl-5 (6) - (5 -methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole, C = 2-trifluoromethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole , D = 5 (6) - {5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, E = 2- (2-fluorophenyl) -5 (6) - (5 -methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, F = 2- (2,4-dimethoxy-phenyl) -5 (6) - (5-methyl-3-oxo- 4,5-Dihydro-2H-6-pyridazinyl) -benzimidazole, G = 2-methylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole , H = 2- (4-methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-8,637,26-pyridazinyl) -benzimidazole, I = 2- (4 -methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, K = 2- (2-pentyl) -5 (6) - (5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride, L = 1-methyl-2- (4-methoxy-phenyl) -5- (5-methyl-3 oxo -4,5-Dihydro-2H-6-pyridazinyl) -benzimidazole M = 1-Benzyl-2-methyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole , compared to N = 2-mercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, O = 2-hydroxy-5 (6) - ( 5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, P = 2-hexylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H -6-pyridazinyl) -benzimidazole, Q = 2-isopropylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, and R = 2-ethoxy- 5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole S = 2-methyl-5 (6) - (2-methyl-3-oxo- 4,5-Dihydro-2H-6-pyridazinyl) -benzimidazole (e.g. 8), T = 2-methyl-5 (6) - (4-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole (e.g. 17), U = 2- (2,4 -dimethoxy-phenyl) -5 (6) - (4-methyl-3-oxo-4,5-dihydro-966372H-6-pyridazinyl) -benzimidazole (e.g. 31), V = 2- (4-methoxy) -phenyl) -5 (6) - (4-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole (e.g. 33), and W = 2- (4-methoxy-phenyl) -5 (6) - (2,4-dimethyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole (e.g. 36).

1. Determination of platelet aggregation by the Bron and Cross method (J. Physiol. 170, 397 (1964)): __

Platelet aggregation was measured in run-flake plasma from healthy subjects. The method measured photometrically and recorded a decrease in optical density after the addition of commercial collagen from Sigma, St. Louis / USA containing 1 mg of collagen fibrils per ml. The accumulation rate (Vmax) was calculated from the slope angle of the density curve. "Optical density" (O.D.) was calculated from the point on the curve where light transmittance was highest. The greatest possible accumulation was swept by adding about 0.01 ml of collagen solution to 1 ml of high-flake plasma.

The results obtained are shown in the following table:

Table I

Compound ec50 'umol / 1 A 0.01 B 34 C 0.1 D 0.12 H 0.08 M_, 1.0_ 2. Determination of antihypertensive and positive inotropic effect in anesthetized cats: _

The studies were performed in cats anesthetized with pentobar-66672 bital sodium (40 mg / kg i.p.) · Animals breathe spontaneously. Arterial blood pressure was measured in the Aorta abdominalis artery with a Statham pressure transducer (P 23 Dc). To demonstrate a positive inotropic effect, left ventricular pressure was measured with a catheter manometer (Millar PC-350 A). Using an analog differentiator, a contractility parameter dp / dtmax was obtained.

The test substances were injected intravenously into the femoral vein. Physiological saline or polydiol 200 was used as the solvent. Each compound was tested in at least 3 cats at a dose of 0.1, 0.5 or 2.0 mg / kg i.v. The duration of action of the tested compounds was at least 1 hour.

The averages obtained are shown in the following table:

Compound Dose mg / kg i.v. Change in blood pressure, mmHg Increase dp / dt,% A 0.1 - 26/24 + 53 B 0.5 + 18/15 + 25 C 0.1 - 65/35 + 91 D 0.5 - 55/48 + 159 E 0.5 - 8/10 + 107 F 0.5 - 28/33 + 89 G 0.1 - 36/40 + 51 H 0.1 +3/0 +23 I 0.5 + 33/15 + 118 K 0.1 - 10/13 + 83 L 0.1 + 14/9 + 17 M 0.1 - 37/33 + 123 N 0.05 - 5 / -5 + 67 O 0.5 - 47 / -38 + 128 P 2.0 - 35 / -40 + 153 Q 0.1 - 17 / -20 + 58 __R __ _0.1_ _ ____ - 15 / -18 _____ + 84 S 0.5 - 10 / -10 + 11 + T 0.5 + 5/3 + 23 + U 0.5 + 15/35 + 10 + V 2.0 - 40/40 - 5 _W 2.0 __'_ - 26_ + Exposure time: 2.5 - 20 minutes 3. Acute toxicity:

The acute toxicity of test compounds was determined approximately in white mice after a single oral dose (observation period: 14 days):

Table III

11 66372 - --------------------- 1 ---

Compound Acute toxicity, mg / kg p.o.

A> 600 (3 animals died 1) C> 450 (6 animals died 0) E> 600 (6 animals died 0) H ~ 600 (6 animals died 3) I> 600 (6 animals died O)

Due to their pharmacological properties, the compounds of the general formula I according to the invention and their optically active antipodes and their physiologically acceptable acid addition salts with inorganic or organic acids are suitable for the treatment of chronic heart failure or Angina Pectoris and / or for the prevention of arterial thromboembolic and arterial obstruction. viruses and viral diseases.

For use, the novel benzimidazoles, optionally in combination with other active ingredients, can be formulated into conventional pharmaceutical forms such as tablets, granules, powders, suppositories, suspensions, ampoules or drops. The single dose is then 1 to 4 times a day from 5 to 200 mg, preferably 15 to 150 mg.

Since the compounds of general formula I may exist in their tautomeric forms 1H or 3H, the substitution site in the benzimidazole nucleus was indicated by 5 (6).

The following examples further illustrate the invention: 12 66372

Example 1 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride (a) 3- [3-nitro 4- (4-Methoxy-benzoylamino) -benzoyl / butyric acid methyl ester 10 g of 3- (3-nitro-4-amino-benzoyl) -butyric acid methyl ester and 10.2 g of 4-ananoic acid chloride are heated to reflux in 100 ml of chlorobenzene, until the 3- (3-nitro-4-amino-benzoyl) -butyric acid methyl ester has completely reacted. The reaction mixture is mixed with activated carbon, filtered and cyclohexane is added to the filtrate, whereupon the product crystallizes. It is filtered off with suction and washed with cyclohexane and petroleum ether.

Yield: 10.7 g (73% of theory)

Melting point: 107-117 ° C.

b) 5-Methyl-6- [3-nitro-4- (4-methoxy-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine_20 ml of 80% hydrazine hydrate are added dropwise with stirring and ice-cooling. To 150 ml of glacial acetic acid. After cooling, 10.7 g of 3- [3-nitro-4- (4-methoxy-benzoylamino) -benzoyl] -butyric acid methyl ester are added and the mixture is heated at reflux for 40 minutes. After cooling, 250 ml of ice water are added, the precipitate is filtered off with suction and washed with ice water.

Yield: 9.8 g (96% of theory)

Melting point: 219 ° C.

c) 5-Methyl-6- [3-amino-4- (4-methoxy-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine_ 9.8 g of 5-methyl-6- [ 3-Nitro-4- (4-methoxy-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine is dissolved in 100 ml of ethanol and hydrogenated for 23 hours at room temperature under a hydrogen pressure of 5 bar in the presence of 1 g of 10% palladium on carbon. The precipitate formed is filtered off with suction and used in the next step without separating the catalyst. Additional product can be obtained from the mother liquor.

Yield: 8.5 g (94.4% of theory).

13 66372 d) 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride_

The product obtained in (c) in 100 ml of glacial acetic acid is heated at reflux for 1.5 hours and then filtered hot through sintered glass. 100 g of ice are added to the filtrate, the orange-yellow precipitate formed is filtered off and washed with dilute acetic acid. The combined filtrates are made alkaline with ammonia. After crystallization, the precipitated product is filtered off with suction and purified on a silica gel column (eluent: methylene chloride / ethanol = 50: 1 and 25: 1). The hydrochloride is precipitated from methanol with ethereal hydrochloric acid.

Yield: 4.45 g (49.8% of theory)

Melting point: 311 ° C (decomposes).

Example 2 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride) 2- (4-methoxy -phenyl) -5 (6) - (1-oxo-2-methyl-3-methoxycarbonyl-1-propyl) -benzimidazole hydrochloride 9.2 g of 5-methyl-6- [3-nitro-4- (4- methoxy-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine is hydrogenated in a mixture of 300 ml of methanol and 3 ml of glacial acetic acid for 2.5 hours at room temperature under 5 bar of hydrogen in the presence of 2 g of percent palladium on carbon. Hydrochloric acid gas is bubbled into the reaction mixture for 2.5 hours under heating at reflux. Ether is then added, filtered off with suction and washed with ether.

Yield: 4.5 g (50.5% of theory)

Melting point: above 300 ° C.

b) 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride In 10 ml of glacial acetic acid is dissolved in 1 ml of 80% hydrazine hydrate, and after cooling 0.43 g of 2- (4-methoxy-phenyl) -5 (6) - (1-oxo-2-methyl-3-methoxycarbonyl-1-propyl) - benzimidazole hydrochloride, the precipitated product is filtered off with suction, washed with 14 66372 water and purified on a silica gel column (eluent: chloroform / methanol = 50: 1). The hydrochloride is precipitated with ethereal hydrochloric acid from ethanol.

Yield: 0.3 g (70.3% of theory)

Melting point: 314 ° C (decomposes).

Example 3 2-Methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 29 g of 5-methyl-6- (3-nitro-4 -acetamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine is hydrogenated in a mixture of 1200 ml of methanol and 100 ml of glacial acetic acid at room temperature for 2.5 hours at 5 bar hydrogen pressure in the presence of 5 g of 10% palladium-on-carbon. The catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in 400 ml of glacial acetic acid and the solution is heated at 100 ° C for 40 minutes. The reaction mixture is poured into one liter of ice and adjusted to pH 8 by adding concentrated ammonia while cooling. The precipitated free base is finally converted to the hydrochloride by dissolving in methanol and adding another hydrochloric acid to the ether end.

Yield: 19.7 g (70.7% of theory)

Melting point: 308 ° C.

Example 4 2-Methyl-5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole 8 g of 2-methyl-5- (6) - (5-methyl-3-oxo-4 (5-Dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride is suspended in 250 ml of glacial acetic acid and a solution of 3 ml of bromine in 30 ml of glacial acetic acid is added dropwise to the suspension with stirring. After the addition, the mixture is kept at 70 [deg.] C. for a further 1 hour, then cooled and the precipitated oily product is crystallized by adding 20 ml of water and heating briefly. Crystals: filtered off with suction, triturated with concentrated ammonia, washed with water and recrystallized from methanol / water. Yield: 5.6 g (89% of theory)

Melting point: above 300 ° C.

15 66372

Example 5 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole _______________

Prepared according to Example 4 using 0.74 g of 2- (4-methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride and 0.33 ml of bromine. The product is purified on a silica gel column (eluent: chloroform / methanol = 50: 1). Yield: 0.35 g (52.6% of theory)

Melting point: above 300 ° C.

Example 6 2- (2,4-Dimethoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ___ a) 2- (2) , 4-Dimethoxy-phenyl) -5 (6) - (1-oxo-2-methyl-3-ethoxycarbonyl-1-propyl) -benzimidazole hydrochloride___

Prepared according to Example 2a) using 12.2 g of 5-methyl-6- [3-nitro-4- (2,4-dimethoxy-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H- pyridazine. The imidazole ring is sealed with ethanolic hydrochloric acid. The product is thoroughly purified and further used in this form.

Yield: 4 g (31.2% of theory).

b) 2- (2,4-Dimethoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

Prepared according to Example 2b) from the product obtained in 6a).

Yield: 0.78 g (21.1% of theory)

Melting point: 266 ° C.

Example 7 2- (4-Methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

Prepar according to Example 2b) 1.5 g of 2- (4-methylphenyl) -16,637,272 (6) - (1-oxo-2-methyl-3-methoxycarbonyl-1-propyl) -benzimidazole hydrochloride.

Yield: 0.24 g (16.5% of theory)

Melting point: 340 ° C (decomposes).

Example 8 2- (4-Methyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride___

Prepared according to Example Id) from 21.5 g of 5-methyl-6- [2-amino-4- (4-methyl-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine (No need to be purified by chromatography).

Yield: 18.8 g (82.7% of theory)

Melting point: 340 ° C (decomposes).

Example 9 2-Cyclopropyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride _______

Prepared according to Example 6 from 2.3 g of 5-methyl-6- (3-nitro-4-cyclopropylcarbonylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine.

Yield: 1.35 g (61.2% of theory)

Melting point: 235-237 ° C (decomposes).

Example 10 1,2-Dimethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimide sol__________________ a) 5-Methyl-6- (3-Amino-4-acetyl-methylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine __________ 0.65 g of 5-methyl-6- (3-nitro-4-acetyl-methylamino-phenyl) ) -3-Oxo-4,5-dihydro-2H-pyridazine is dissolved in 30 ml of ethanol and 0.5 ml of 80% hydrazine hydrate and 0.5 g of Raney nickel are added to the solution, followed by heating at 30 ° C for 10 minutes: in.

66372

The catalyst is filtered off, glacial acetic acid is added to the filtrate and evaporated in vacuo. The residue is used directly.

b) 1,2-Dimethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole _______________

Prepared according to Example Id) from the product obtained in 10a. Yield: 0.15 g (27.4% of theory)

Melting point: above 250 ° C.

Example 11 2- (2-Fluoro-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 3.2 g of 5-methyl -6- [3-Amino-4- (2-fluoro-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine is suspended in 150 ml of isopropanol and hydrochloric acid gas is bubbled into the mixture for 2 hours while refluxing. It is then evaporated and the residue is crystallized by trituration with ether.

Yield: 1.35 g (40% of theory)

Melting point: 295 ° C.

Example 12 2-Phenyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

Prepared according to Example 11 from 2.0 g of 5-methyl-6- (3-amino-4-benzoylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine.

Yield: 0.85 g (40.5% of theory)

Melting point: 335 ° C.

Example 13 2-Isopropyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

6.2 g of 5-methyl-6- (3-amino-4-isobutyrylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are prepared according to Example 11.

18 66372

Yield: 4.7 g (71% of theory)

Melting point: 270-272 ° C.

Example 14 2-n-Pentyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ___________________

1.8 g of 5-methyl-6- (3-amino-4-caproylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are prepared according to Example 11.

Yield: 0.8 g (41.8% of theory)

Melting point: 244 ° C.

Example 15 2- (4-Chloro-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ___________.

1.45 g of 2- (4-chloro-phenyl) -5 (6) - (1-oxo-2-methyl-3-methoxycarbonyl-1-propyl) -benzimidazole hydrochloride are prepared according to Example 2b).

Yield: 0.32 g (23% of theory)

Melting point: sinter from 78 ° C.

Example 16 2-Trifluoromethyl-5 (6) -5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ____________ 11 g of 5-methyl-6- (3,4-diamino- phenyl) -3-oxo-4,5-dihydro-2H-pyridazine and 70 ml of trifluoroacetic acid are heated at reflux for 2 hours. It is then evaporated to dryness in vacuo, ice water is added and the mixture is adjusted to ammonia. The mixture is extracted with ethyl acetate, the ethyl acetate phase is evaporated and the residue is crystallized from 50% ethanol by adding activated carbon.

Yield: 6.4 g (50% of theory)

Melting point: 278-280 ° C.

Example 17 66372 19 2-Trifluoromethyl-5 (6) - (5-methyl-3-oxo-2H-6-pyridazinyl) -benzimidazole___________________________

Prepared according to Example 4 from 6 g of 2-trifluoromethyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole. . Yield: 0.8 g (13.5% of theory)

Melting point: above 300 ° C (from ethanol).

Example 18 5 (6) - (5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride _____________

Prepared according to Example 16 from 2.0 g of 5-methyl-6- (3,4-diaminophenyl) -4-oxo-4,5-dihydro-2H-pyridazine and formic acid. The hydrochloride is precipitated from methanol with ethereal hydrochloric acid and recrystallized from ethanol / ether.

Yield: 0.6 g (28.9% of theory)

Melting point: 300 ° C (decomposes).

Example 19 2-Mercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 5__ g 5.2 g of potassium hydroxide are dissolved in a mixture of 50 ml of ethanol and 6.6 ml of water, followed by the addition of 3.84 g of carbon disulphide and 11.0 g of 5-methyl-6- (3,4-diamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine and heating 3 hours at reflux. Dilute with water, dilute with glacial acetic acid and separate the precipitated product with suction and wash with water.

Yield: 10.6 g of crude product (94.3% of theory)

The product is purified on a silica gel column (eluent: chloroform / ethanol = 9: 1).

Melting point: above 300 ° C.

2-Methylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole _______

Example 20 66372 6/0 g of the crude product prepared in Example 19 are dissolved in 250 ml of dimethylformamide and then 3.3 g of methyl iodide and 1.4 g of sodium bicarbonate are added. The mixture is stirred for 1 hour at room temperature, and for 1 hour at 50 ° C. The solvent is evaporated in vacuo, the residue is triturated with water and purified on a silica gel column. Yield: 1.5 g (23.8% of theory)

Melting point: 268 ° C (decomposes).

Example 21 2-Cyclohexyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ____

9.7 g of 5-methyl-6- (3-nitro-4-cyclohexylcarbonylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are prepared according to Example 1e) and Id). The hydrochloride is precipitated from acetone with ethereal hydrochloric acid and recrystallized from ethanol.

Yield: 2.3 g (24.7% of theory)

Melting point: 315-320 ° C.

Example 22 2- (4-tert-Butyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride hydrate__ a) 5- Methyl-6- [3-amino-4- (4-tert-butyl-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine_

Prepared according to Example 1e) from 12.6 g of 5-methyl-6- [3-nitro-4- (4-tert-butyl-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H -pyridazine. After filtration of the catalyst, the product is precipitated with water.

Yield: 9.9 g (84.5% of theory)

Melting point: 215-217 ° C.

b) 2- (4-tert-butyl) phenyl 5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole hydrochloride hydrate 21 66372

Prepared according to Example Id) from the product obtained in a). Yield: 7.9 g (73% of theory)

Melting point: 294-298 ° C.

Example 23 2- (2-Pentyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride (a) 5-methyl-6- [3 -Amino-4- (2-methyl-valeryl-amino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine_

Prepared according to Example 22a) from 12.5 g of 5-methyl-6- [3-nitro-4- (2-methyl-valeryl-amino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine . After addition of water, the product is extracted with ethyl acetate.

Yield: 4.2 g (36.6% of theory)

Melting point: 179-181 ° C.

b) 2- (2-Pentyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl-benzimidazole) -hydrochloride

Prepared according to Example Id) from the product obtained in a). Yield: 1.3 g (28.4% of theory)

Melting point: sintered from 150 ° C.

Example 24 2- (n-Hexyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 5-Methyl-6- (3-methyl-6- amino-4-heptanoyl-amino-phenyl) -3-oxo-4,5-di-hydro-2H-pyridazine ___

According to Example 22a) 11.75 g of 5-methyl-6- (3-nitro-4-heptanoylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine are prepared. Yield: 8.0 g (78% of theory)

Melting point: 158-1600 (b) 2- (n-Hexyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidateole hydrochloride 22 66372

Prepared according to Example Id) from the product obtained in a). Yield: 6.2 g (73.5% of theory)

Melting point: 225-227 ° C.

Example 25 1-Cyclohexyl-2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole-1.3 g 5-methyl-6- (3 -amino-4-cyclohexylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine and 50 ml of glacial acetic acid are heated at reflux for 6 hours. The reaction mixture is poured onto ice, neutralized with ammonia and the precipitated product is purified on a silica gel column (eluent: methylene chloride / acetone = 10: 0 to 9: 1).

Yield: 0.4 g (28.5% of theory)

Melting point: 259-262 ° C (decomposes).

Example 26 2-Hydroxy-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazoline 2 g of 2-methylmercapto-5 (6) - (5-methyl- 3-Oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole is dissolved in 100 ml of glacial acetic acid, 10 ml of 30% hydrogen peroxide are added to the solution and heated at 50 ° C for 6 hours. After 3 and 4 hours, a further 2 ml of hydrogen peroxide are added each time. Most of the reaction mixture is evaporated in vacuo, then poured into water and the precipitate is recrystallized from ethanol / cyclohexane.

Yield: 0.37 g (21% of theory)

Melting point: above 300 ° C.

Example 27 23 66372 2- (2-Methoxy-4-methylmercapto-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_2 g 5-Methyl-6- [3-amino-4- (2-methoxy-4-methylmercapto-benzoylamino) -phenyl] -3-oxo-4,5-dihydro-2H-pyridazine is heated in 100 ml of glacial acetic acid 2 At reflux for 5 hours, the reaction mixture is filtered hot and, after cooling, stirred in a mixture of ice and concentrated ammonia. The precipitated product is recrystallized from methylene chloride after drying.

Yield: 1.1 g (57.7% of theory)

Melting point: 155-165 ° C (decomposes).

Example 28 1-Cyclopropyl-2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole) 5-Methyl-6- (3-amino -4-Cyclopropylamino-phenyl) -3-oxo-4,5-dihydro-2H-pyridazine __-5.8 g of 5-methyl-6- (3-nitro-4-cyclopropylamino-phenyl) -3-oxo-4,5 -dihydro-2H-pyridazine is hydrogenated in a mixture of 100 ml of ethanol and 20 ml of glacial acetic acid under 5 at hydrogen pressure in the presence of 0.5 g of 10% palladium-on-carbon. 120 ml of glacial acetic acid are added, the catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is used without further purification.

b) 1-Cyclopropyl-2-methyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole _______

Prepare according to Example 25 from the product obtained in a) and 30 ml of glacial acetic acid (heating time: 3 hours, no need to clean on a column).

Yield: 4.6 g (81.5% of theory)

Melting point: 246-250 ° C.

24 I Example 29 66372 j 2 “Hexylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ___ ι j Prepared according to Example 20 2.6 g of 2-mercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole I and 1.7 g of 1-bromohexane (reaction temperature: 80 ° C, reaction time: 7 hours).

j Yield: 1.0 g (29% of theory) J Melting point: 172 ° C (decomposes, from isopropanol / petroleum ether).

i

Example 30 1-Methyl-2- (4-methoxy-phenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole _____ 6.4 g of 5-methyl-6- [ 3-Nitro-4- (N-methyl- (4-methoxy-benzoyl) -amino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one is treated with hydrogen at 5 bar for 2.5 hours at room temperature. In 100 ml of ethanol in the presence of 0.6 g of 10% palladium on carbon. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is purified by chromatography on silica gel (eluent: methylene chloride / ethanol 19: 1 to 9: 1). The corresponding fractions are combined and the product is crystallized by trituration with ether.

Yield: 0.15 g (3% of theory)

Melting point: 248-249 ° C.

Example 31 1-Benzyl-2-methyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ____ a) 5-Methyl-6- (3-amino- 4-Benzylamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one _____ 6.75 g of 5-methyl-6- (3-nitro-4-benzylamino-phenyl) -4,5-dihydro-2H- Pyridazin-3-one in a mixture of 100 ml of ethanol and 20 ml of glacial acetic acid is treated with 0.7 g of 10% palladium-on-carbon catalyst under 5 bar of hydrogen at room temperature for 3.5 hours. The catalyst is filtered off, the filtrate is evaporated and the residue is used in the next step without purification.

b) 1-Benzyl-2-methyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_

The product obtained in a) is taken up in 100 ml of glacial acetic acid and heated at reflux for 2.5 hours. Ice is then added, the mixture is adjusted to ammonia and the precipitated product is purified by chromatography on silica gel (eluent: first pure methylene chloride, then more and more acetone until the mixture ratio of methylene chloride and acetone = 10: 3). After evaporation of the eluent, the bed crystallizes on trituration with ether.

Yield: 2.2 g (33% of theory)

Melting point: 279 ° C.

Example 32 1-Cyclohexyl-2-methyl-6- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_

1.3 g of 5-methyl-6- (3-amino-4-cyclohexylaminophenyl) -4,5-dihydro-2H-pyridazin-3-one are prepared according to Example 31.

After chromatography on silica gel (eluent: methylene chloride / acetone = 10: 0 to 9: 1) 1-cyclohexyl-2-methyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6 -pyridazinyl) -benzimidazole can be obtained in pure form.

Yield: 0.1 g (7% of theory)

Melting point: 237 ° C (decomposes)

Example 33 2-Isopropylmercapto-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_ 3.4 g of 2-mercapto-5 (6) - ( 5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole is dissolved in 50 ml of dimethylformamide, 1.62 g of isopropyl bromide and 1.1 g of sodium bicarbonate are added and the mixture is heated on a steam bath for 20 hours. The solvent is evaporated in vacuo and the residue is purified by chromatography on silica gel (eluent: 26 66372 chloroform / ethanol 9: 1).

Yield: 0.45 g {11% of theory)

Melting point: 120-121 ° C.

Example 34 2- (2-Methoxy-4-methylsulfinyl-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 0.9 g of 2- (2-Methoxy-4-methylmercapto-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole is dissolved in 50 parts of glacial acetic acid and a solution of 0 , 24 g of 30% hydrogen peroxide in 10 ml of glacial acetic acid. The reaction mixture is allowed to stand for 22 hours at room temperature, then poured onto ice, adjusted to ammonia and the precipitate formed is purified by chromatography on silica gel (eluent: methylene chloride / ethanol 19: 1). After evaporation of the eluent, the residue is triturated with acetone and ether to crystallize.

Yield: 0.5 g (53% of theory)

Melting point: 173-180 ° C.

Example 35 2- (1-Phenyl-2-propyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 5.1 g of 5- methyl 6- [3-amino-4- (3-phenyl-isobutyrylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one in 100 ml of glacial acetic acid is heated at reflux for 1.5 hours. The glacial acetic acid is distilled off, the residue is taken up in a mixture of ethanol and acetone and the hydrochloride is precipitated with ethereal hydrochloric acid. The hydrochloride crystallizes completely on trituration with a mixture of ether and ethanol.

Yield: 2.4 g (45% of theory)

Melting point: 235-239 ° C.

Example 36 2-Cycloheptyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ______________

Prepared according to Example 35 using 5.5 g of 5-methyl-6-27,6372 (3-amino-4-cycloheptylcarbonylamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one.

Yield: 4.2 g (73% of theory)

Melting point: 255-259 ° C.

Example 37 2- (4-Hydroxyphenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride__

6.3 g of 5-methyl-6- [3-amino-4- (4-hydroxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one are prepared according to Example 35.

Yield: 4.4 g (66% of theory)

Melting point: 350-354 ° C.

Example 38 2- (4-n-Hexyloxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-β-pyridazinyl) -benzimidazole hydrochloride

5.7 g of 5-methyl-6- [3-amino-4- (4-n-hexyloxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazine are prepared according to Example 35. 3-one.

Yield: 3.55 g (60% of theory)

Melting point: 278-282 ° C.

Example 39 2- (3,4,5-Trimethoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-pyridazinyl) -benzimidazole ____

Prepared according to Example 35 from 14.9 g of 5-methyl-6- [3-amino-4- (3,4,5-trimethoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazine- 3-one. After evaporation of glacial acetic acid, the residue obtained is extracted with boiling ethanol. Evaporation of ethanol and stirring with ether gives the compound in crystalline form.

Yield: 9.2 g (65% of theory)

Melting point: 295-300 ° C.

28 66372

Example 40 1- (3-Methyl-butyl) -2-methyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ________ a) 5-methyl-6- [ 3-Amino-4- (N-acetyl-N- (3-methyl-butyl) -amino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one _____ 6 g 5-methyl-6- / 3 -Nitro-4- (N-acetyl-N- (3-methyl-butyl) -amino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one is dissolved in 150 ml of ethanol, 4 g of Raney are added. nickel and 3 ml of 98% hydrazine hydrate and stirred for 30 minutes at room temperature. The catalyst is filtered off, the filtrate is evaporated and the residue is used without purification.

b) 1- (3-Methyl-butyl) -2-methyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_

Prepared according to Example 35 from the product obtained in a). Purify by chromatography on silica gel (eluent: methylene chloride / ethanol = 9: 1).

Yield: 2.2 g (43% of theory)

Melting point: 247 ° C.

Example 41 1-Benzyl-2-trifluoromethyl-5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole __________________

5.2 g of 5-methyl-6- (3-nitro-4-benzylamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one are prepared according to Example 31.

Yield: 1.4 g (23% of theory)

Melting point: 210-212 ° C.

Example 42 2-Methyl-5 (6) - (5-ethyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_____

1.2 g of 5-ethyl-6- (3-nitro-4-amino-phenyl) -4,5-dihydro-2H-pyridazin-3-one are prepared according to Example 31.

29

Yield: 0.5 g (41% of theory) 6 6 3 V 2

Melting point: 291-295 ° C.

Example 43 2- (4-Methoxy-phenyl) -5 (6) - (5-ethyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

Prepared according to Example 35 using 3.6 g of 5-ethyl-6- [3-amino-4- (4-methoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one.

Yield: 3.6 g (91% of theory)

Melting point: 178-198 ° C.

Example 44 2- (3-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_

2.2 g of 5-methyl-6- [3-amino-4- (3-methoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one are used in the preparation of Example 35. Purify by chromatography on silica gel (eluent: methylene chloride / ethanol = 19: 1).

Yield: 0.72 g (34% of theory)

Melting point: 295-298 ° C.

Example 45 2- (2-Bromo-5-methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole _________

Prepared according to Example 44 from 2.8 g of 5-methyl-6- [3-amino-4- (2-bromo-5-methoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3- one.

Yield: 0.75 g (28% of theory)

Melting point: sintered from 70 ° C.

30 66372

Example 46 2-Undecyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ___________________________ a) 5-Methyl-6- (3-amino-4-undecanecarbonylamino) -phenyl) -4,5-dihydro-2H-pyridazin-3-one ___________ 10 g of 5-methyl-6- (3-nitro-4-undecanecarbonylamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one -one is dissolved in 100 ml of dimethylformamide and treated with hydrogen at room temperature at 5 bar for 1.2 hours in the presence of 1 g of 10% palladium on carbon. The catalyst is filtered off, then poured into ice water, extracted with methylene chloride and the organic phase is evaporated, the oily residue is used directly.

b) 2-Undecyl-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole_________

The product obtained in a) is dissolved in 100 of any glacial acetic acid and heated at reflux for one hour. The solution is evaporated to half volume, poured onto ice and adjusted to ammonia. The precipitated product is recrystallized from ethyl acetate. The compound is further purified by chromatography of the mother liquors (silica gel, eluent: methylene chloride / ethanol = 19: 1).

Yield: 7.7 g (87% of theory)

Melting point: 165 - 169 ° C (decomposes)

Example 47 2-Methyl-5 (6) - (5-n-butyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole ___________

Prepared according to Example 31 from 4 g of 5-n-butyl-6- (3-nitro-4-amino-phenyl) -4,5-dihydro-2H-pyridazin-3-one.

Yield: 1.7 g (43% of theory)

Melting point: 184-186 ° C (decomposes).

31

Example 48 6 6 3 7 2 2- (4-Methoxy-phenyl) -5 (6) - (5-n-butyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ______

Prepared according to Example 44 from 4.2 g of 5-n-butyl-6- [3-amino-4- (4-methoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3- one. The hydrochloride is precipitated from ethyl acetate with ethereal hydrochloric acid.

Yield: 3.2 g (73% of theory)

Melting point: 160-190 ° C.

Example 49 2- (1-Phenyl-1-ethyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

Prepared according to Example 35 from 3 g of 5-methyl-6- [3-amino-4- (2-phenyl-propionyl) -phenyl] -4,5-dihydro-2H-pyridazin-3-one. Yield: 1.6 g (51% of theory)

Melting point: sintered from 85 ° C.

Example 50 i.

2-Ethoxy-5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride _____________ 10.9 g of 5-methyl-6- (3,4-diamino) -phenyl) -4,5-dihydro-2H-pyridazin-3-one is suspended in 12.5 g of ortho-carbonic acid tetraethyl ester, 10 ml of dimethyl sulfoxide are added to the suspension and heated at reflux for 1.5 hours. The solvent is distilled off and the oily residue is crystallized by trituration with ether / chloroform.

The hydrochloride is precipitated with ethereal hydrochloric acid from acetone / ethanol 1: 1 and recrystallized from ethanol / isopropanol.

Yield: 7.6 g (49% of theory)

Melting point: above 300 ° C.

Example 51 6 6 3 7 2 32 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride. 1 g of 2- (4-hydroxy-phenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride is suspended in 50 ml of methanol and 0.34% is added. g of sodium methylate. After a clear solution has formed, 2.52 g of dimethyl sulfate and a further 0.34 g of sodium methylate are added portionwise. The total reaction time is 6 hours at room temperature. The reaction mixture is poured onto ice, neutralized and the precipitate is purified on a silica gel column (eluent: methylene chloride / ethanol 50: 1 to 25: 1). The hydrochloride is precipitated with ethereal hydrochloric acid from methanol.

Yield: 0.59 g (52% of theory)

Melting point: 311 ° C (decomposes).

Example 52 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride) 5-Methyl-6- [3-amino-4- (4-methoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one _______________ 203 g of 5-methyl-6- [3-nitro-4- (4-methoxy) -Benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one is dissolved in 1.7 liters of dimethylformamide and treated for 2 hours under 5 bar of hydrogen in the presence of 20 g of 10% palladium on carbon. After filtration of the catalyst, the filtrate is poured into 7.5 liters of ice water and the precipitated product is dried at 120 ° C.

Yield: 182 g (97% of theory)

Melting point: 253 ° C.

b) 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ______ 180 g of 5-methyl-6- [3-Amino-4- (4-methoxy-benzoylamino) -phenyl] -4,5-dihydro-2H-pyridazin-3-one is suspended in 1.5 liters of glacial acetic acid and heated at reflux for 30 minutes. 350 ml of solvent are then distilled off under reduced pressure. The rest of the mixture is treated with activated carbon at 70 ° C, separated by filtration and, after cooling to 20 ° C, the filtrate is added dropwise with stirring to a mixture of 2 liters of ice-water and 1.5 liters of concentrated ammonia. The temperature is kept below 20 ° C by adding ice. The precipitated product is washed with water and dried at 80 ° C. The base is converted into the hydrochloride by dissolving in isopropanol, adding concentrated hydrochloric acid and diluting with 2 liters of acetone. The free base still present in the mother liquors is treated accordingly.

Yield: 176 g (93% of theory)

Melting point: 300-306 ° C (decomposes).

Example 53 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride 0.22 g of 5-methyl- 6- (3,4-Diamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one and 0.2 g of 4-methoxy-benzamidine hydrochloride are triturated and then heated at 160 ° C for 40 minutes. . The reaction mixture is purified by chromatography on silica gel (eluent: methylene chloride / ethanol 50: 1 to 25: 1) and the hydrochloride is precipitated with ethereal hydrochloric acid from methanol.

Yield: 0.04 g (10% of theory)

Melting point: 305-307 ° C (decomposes).

Example 54 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride

A mixture of 0.22 g of 5-methyl-6- (3,4-diaminophenyl) -4,5-dihydro-2H-pyridazin-3-one, 0.15 g of 4-methoxybenzonitrile and 0, 17 g of p-toluenesulfonic acid, heated for 30 minutes at 160 ° C. The reaction mixture is worked up as in Example 32.

Yield: 0.06 g (16% of theory)

Melting point: 304-309 ° C (decomposes).

34 66372

Example 55 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride__

Prepared according to Example 54 by using 0.22 g of potassium tert-butylate instead of p-toluenesulphonic acid.

Yield: 0.03 g (8% of theory)

Melting point: 305-306 ° C (decomposes).

Example 56 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ____ 0.22 g of 5-methyl- 6- (3,4-Diamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one and 0.42 g of S-methyl-4-methoxy-thiobenzoic acid morpholide iodide are heated in 3 ml. ethylene glycol for 10 minutes at 140 ° C. After cooling, it is poured into ice water, the product is taken up in ether and purified according to Example 53.

Yield: 0.13 g (35% of theory)

Melting point: 309-311 ° C (decomposes).

Example 57 2- (4-Methoxy-phenyl) -5 (6) - (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole hydrochloride ________ 0.22 g of 5-methyl -6- (3,4-Diamino-phenyl) -4,5-dihydro-2H-pyridazin-3-one and 0.29 g of 4-methoxy-benzoic acid phenyl ester are heated at 150 ° C for 30 minutes. The reaction mixture is worked up according to Example 53.

Yield: 0.23 g (62% of theory)

Melting point: 108-111 ° C (decomposes).

Claims (1)

A process for the preparation of pharmacologically active benzimidazoles substituted in the 5- or 6-position by a pyridazinone ring of the formula IB h 3 IR 1 - {XJ- (I> wherein A and B are each a hydrogen atom or together another bond, r 1 is a hydrogen atom, a trifluoromethyl group, 1 An alkyl group having 11 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a hydroxy or mercapto group optionally substituted by an alkyl group having 1 to 6 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, or a phenyl group which may be mono-, di - or trisubstituted by a halogen atom, an alkyl group having 1 to 4 carbon atoms, a methylsulfinyl, hydroxy, mecapto, methyl mercapto and / or alkoxy group containing 1 to 6 carbon atoms, R 2 is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, 3 A cycloalkyl group having 6 to 6 carbon atoms or a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, and r 3 is an alkyl group having 1 to 6 carbon atoms, and a physiologically acceptable acid addition salt thereof and with inorganic or organic acids, characterized in that a) the compound of general formula (II) T (II) ^ · Y 36 6 6 3 7 2 optionally prepared in the reaction mixture is cyclized in which A, B, 1 * 2 and Rj have the same meaning as above. , one of X and Y is a hydrogen atom and the other of X and Y or both X and Y is a group of the formula Z1, Z2 -c-4 wherein and Z1 »which may be the same or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups or Z 1 and Z 2 together are an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, and R 4 is the same as an amino group substituted above with R 1 or an alkyl group optionally having 1 to 4 carbon atoms, or an alkali salt thereof, when R 4 is a mercapto group, or b) a carboxy of general formula (III) overacid o A B Rx-J | - | - - C - C - CH - COOH (III) 'n R 3 H in which A, B and R 1 - R j are as defined above, or an ester, amide or halide thereof is reacted with hydrazine and then by method a or b the obtained compound of general formula (I) in which A and B are each a hydrogen atom is, if desired, converted by dehydration into a compound of general formula (I) in which A and B together are another bond, and / or the obtained compound of general formula (I) in which R 1 is a hydroxy or mercapto group or a phenyl group mono-, di- or trisubstituted by a hydroxy and / or mercapto group and / or R 2 is a hydrogen atom is converted by alkylation into the corresponding alkoxy, alkyl mercapto and / or alkyl compound of general formula (I) and / or or the resulting compound of general formula (I) wherein R 1 is a phenyl group substituted by at least one alkyl mercapto group is converted by oxidation to the corresponding alkylsulfinyl-phenyl compound of general formula (I) and / or the obtained compound of general formula (I) a ste having an alkyl mercapto group is converted by oxidation and subsequent cleavage of the hydrolytically formed alkylsulfinyl or alkylsulfonyl group to the corresponding hydroxy compound of general formula (I) and / or the resulting compound of general formula (I) is converted into its physiologically acceptable acid addition salts with its organic addition salts. ; 38 6 6 3 7 2 i and I For the preparation of the armacological network in the 5- or 6-position with pyridazinone substituents benzimidazoler with formula! I r2 där A och B bägge Mr en väteatom eller tillsammans andra bindning, är en väteatom, en trifluoromethylgroup, en alkylgrupp med 1-11 kolatomer, en cycloalkylgroup med 3-7 kolatomer, en optionally medg alkylkyl med 1-6 kolatomer substituerad hydroxy- or a market group, with phenylalkyl having 1-3 cholaters and alkyl or phenyl groups having a mono-, di- or trisubstituted group with halogen, 1-4 cholata alkyl groups, methylsulfinyl, hydroxy-, mercapto-, methylmercapto and / or alkoxy group having 1-6 cholaters, R 2 is a hydrogen atom, an alkyl group having 1 to 5 cholatomers, a cycloalkyl group having 3 to 6 cholatomers or a phenylalkyl group having 1 to 3 cholatomers and alkyl groups, and R 1 is an alkyl group of 1- 6 collatants, and with physiologically warm cyano-addition salts with organic or organic syrups, with the aid of formula (a) BX R3 I o ^ IY 39 66372 from A, B, R2 and R3 are selected from the group consisting of ovan, den ena av gruppecna X oc h Y är en väteatom och den andra av grupperna X och Y eller bSde Gruppen X och Y avser en grupp med formuleln z2 -C- r4 där och Z2 * som kan vara lika eller olika, avser eventuellt substitu-tuerade aminoogrupper eller eventuellt med lägre alkyl groups substituted by hydroxy- or mercaptogroups with z1 and z2 are similarly substituted with 1-3 cholatomic alkyl groups substituted with imino, alkylenedioxy or alkylenedioxy, with 2 or 3 cholera, and R4 is selected from the group consisting of an alkyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms, or an alkali group, and R4 is a mercapto group, cyclized, or b) a carboxyl group having the formula (III) / t 0 AA // Tl I "'' R · ^ - (f --C - C - CH - COOH * 3 (III> där A, B och R eventually and for example, no further payment is required then formula (I) of A and B is a compound, the genome being dehydrated to a compound of formula (1), and A and B of the same image and / or binding to a compound of formula (I), R en hydroxy- or mercapto group or phenyl group, which is mono-, di- or trisubstituted with hydroxy- and / or mercapto group, och / eller